Project Summary In our interim analysis of the MATCH cohort, an NIH funded study of muscle function and aging in middle aged (50-65) adults with and without HIV infection, we observe an unexpected and novel finding that the frequency of central nuclei in muscle fibers, indicative of muscle injury or damage, are elevated in muscle biopsies obtained from HIV+ adults, despite effective ART when compared to uninfected adults. Notably, and relevant to this R21 application, we also observe that subjects on efavirenz (EFV) containing regimens appear to be at lower risk for the myopathy. Our overall hypothesis is that ART regimens influence the risk for a novel HIV- associated myopathy, i.e., central nuclear myopathy (CNM), ultimately increasing the risk for physical function impairment. To further characterize the role of ART regimen in our observed HIV-associated CNM, as well as potential physical function correlates, biospecimens (blood, muscle biopsy) and physical function data that is being collected as part of an ongoing MATCH study (NIH R01AI108541, PI: M. Montano) will be leveraged in a cross-sectional analysis to 1) evaluate candidate causal pathways for CNM in muscle biopsies, notably the ryanodine receptor 1 (RyR1) pathway, to determine their potential relevance to HIV and ART regimen use and 2) evaluate physical function in association with CNM and ART regimen use, based on our current laboratory physical function assessments and to collect activity using a physical activity tracking device, a triaxial accelerometer. This R21 proposal is in response to PAR-15-282 (HIV and Aging) and NOT-15-137 (NIH Research Priorities), which has set a high priority for studies on ?HIV-associateed comorbidities and premature aging associated with long-term HIV disease and antiretroviral therapy?.